New method to improve nk cells cytotoxicity

Abstract

A combination of retinoic acid, an anti-O-acetylated disialoganglioside (OAcGD2) compound and an anti-PD1/PD-L1 compound for treating a cancer, particularly neuroblastoma, in a subject in need thereof. The inventors focused on immunotherapeutic strategies targeting OAcGD2, believing they could address critical neuropathic pain side effects associated with anti-GD2 mAb infusions. They reported mAb 8B6 targeting OAcGD2 displays antitumor activity in NB tumor models, with induction of ADCC similarly to anti-GD2 mAbs. From this, the inventors interrogated whether 13-cis-RA and retinoic acid generally, may augment anti-NB efficiency of mAb 8B6 therapy. They found cooperative interaction of 13-cis-RA and mAb 8B6 treatment in inhibiting the NB growth in vivo. However, this combination regimen also coordinates PD-1/PD-L1 upregulation, which hinders a long-term activation of NK cells and allows tumor cell to relapse. Importantly this counter therapeutic effect can be leveraged with PD1 blockade to improve the therapeutic response of the mAb 8B6+13-cis-RA regimen.

1 - 15 . (canceled) 
     
     
         16 . A method for treating a cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising retinoic acid, an anti-O-acetylated disialoganglioside (OAcGD2) compound and an anti-PD1 or anti-PD-L1 compound. 
     
     
         17 . The method according to  claim 16 , wherein said pharmaceutical composition further comprises at least one anti-cancer agent. 
     
     
         18 . A method for treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of retinoic acid, an anti-O-acetylated disialoganglioside (OAcGD2) compound and an anti-PD1 or anti-PD-L1 compound. 
     
     
         19 . The method according to  claim 18 , wherein the retinoic acid is 13-cis-retinoic acid. 
     
     
         20 . The method according to  claim 18 , wherein the cancer is a neuroblastoma, a glioblastoma, a small-cell lung carcinoma or a breast cancer. 
     
     
         21 . The method according to  claim 18 , wherein the anti-OAcGD2 compound is an antibody comprising the following complementary-determining regions (CDRs): 
       
         
           
                 
                 
               
                     
                   CDR1: 
                 
                     
                   (SEQ ID NO: 1) 
                 
                     
                   EFTFTDYY; 
                 
                     
                     
                 
                     
                   CDR2: 
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   IRNRANGYTT; 
                 
                     
                     
                 
                     
                   CDR3: 
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   ARVSNWAFDY; 
                 
                     
                     
                 
                     
                   CDR4: 
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   QSLLKNNGNTFL; 
                 
                     
                     
                 
                     
                   CDR5: 
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   KVS; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   CDR6:  
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   SQSTHIPYT. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         22 . The method according to  claim 18 , wherein the anti-OAcGD2 compound is a humanized antibody. 
     
     
         23 . The method according to  claim 18 , wherein the anti-OAcGD2 compound is an antibody comprising:
 a) a light chain variable region (VL) having the amino acid sequence SEQ ID NO: 7, or a sequence having a percentage of identity of at least 85% with SEQ ID NO: 7; and   b) a heavy chain variable region (VH) having the amino acid sequence SEQ ID NO: 8, or a sequence having a percentage of identity of at least 85% with SEQ ID NO: 8.   
     
     
         24 . The method according to  claim 18 , wherein the anti-OAcGD2 compound is an antibody having a sequence comprising:
 a heavy chain variable region (VH) sequence selected from the group consisting of SEQ ID NO: 9 (“VH49A”), SEQ ID NO: 10 (“VH72A”), SEQ ID NO: 11 (“VH49BHS”), SEQ ID NO: 12 (“VH72BHNPS”), SEQ ID NO: 16 (“VH49BHSs”), SEQ ID NO: 17 (“VH72BHNPSs”), or a variant thereof; and/or   a light chain variable region (VL) sequence selected from the group consisting of SEQ ID NO: 13 (“VL30A”), SEQ ID NO: 14 (“VL28A”), SEQ ID NO: 15 (“VL28Bs01/A2”), SEQ ID NO: 18 (“VL30As”), SEQ ID NO: 19 (“VL28B01/A2”), or a variant thereof.   
     
     
         25 . The method according to  claim 18 , wherein the anti-O-acetylated disialoganglioside (OAcGD2) compound and the anti-PD1 or anti-PD-L1 compound are a multi-specific antibody having at least two antigen binding sites directed to OAcGD2 and to PD1 or PD-L1. 
     
     
         26 . The method according to  claim 25 , wherein the multi-specific antibody is a bi-specific antibody directed to OAcGD2 and to PD1 or PD-L1, or a derivative thereof. 
     
     
         27 . The method according to  claim 25 , wherein the multi-specific antibody is a trivalent or tetravalent antibody comprising at least two antigen binding sites directed to OAcGD2 and at least one antigen binding site directed to PD1 or PD-L1. 
     
     
         28 . A method for treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of allogenic NK cells treated with retinoic acid, an anti-O-acetylated disialoganglioside (OAcGD2) compound and an anti-PD1 or anti-PD-L1 compound. 
     
     
         29 . The method according to  claim 17 , wherein the at least one anti-cancer agent is interleukin-2 (IL-2) and/or an anti-disialoganglioside (anti-GD2) antibody. 
     
     
         30 . The method according to  claim 18 , wherein the cancer is a neuroblastoma. 
     
     
         31 . The method according to  claim 18 , wherein retinoic acid, the anti-O-acetylated disialoganglioside (OAcGD2) compound and the anti-PD1 or anti-PD-L1 compound are administered simultaneously, separately, or sequentially.